Project Summary Sex and gender are potent influencers of the etiology, presentation, and prognosis of essentially every neuropsychiatric disorder. However, we have a fundamental gap in knowledge in understanding how sex interacts with other contributors to neuropsychiatric risk, such as genetic variants. These genetic variants may not have the same biobehavioral impacts across male and female brains. One such genetic factor, copy number variation at the 16p11.2 locus, is strongly associated with a broad spectrum of male-biased neurodevelopmental diagnoses, including autism and psychosis at the level of genome-wide significance. Male mice with a hemideletion at the syntenic 16p11.2 locus display profound alterations in reward-guided decision making and striatal biology, but these are substantially mitigated in female mice carrying the same hemideletion. This animal model is thus ideally positioned to reveal how sex interacts with genetic factors that alter neurodevelopment to produce male vulnerability. Strong evidence implicates striatal circuits in reward- guided choice behavior. We will pursue three Aims assessing whether altered functional activation of striatal circuits in male 16p11.2 hemideletion animals, in comparison with wildtype males and 16p11.2 hemideletion females, provides explanatory power for behavioral alterations in these males. In each case, we will test whether sex differences in striatal circuit function interact with or mitigate the impact of 16p11.2 hemideletion on these circuits. In Aim 1, we will measure dopamine inputs into the dorsomedial striatum and nucleus accumbens core during decision making to determine if these signals are leading to striatal dysfunction in males, and if dopamine release in females is normalized. In Aim 2, we will measure medium spiny neuron outputs from the dorsomedial striatum and nucleus accumbens during the same decision epochs to determine what aspects of choice and reward are being signaled in 16p11.2 hemideletion males versus females. Finally in Aim 3, we will expand our scope to measure functional connectivity to the striatum across the brain using resting state functional magnetic resonance imaging, asking in particular if cortical inputs to specific striatal compartments are impacted by 16p11.2 hemideletion in a sex-dependent manner.